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Int. J. Mol. Sci. 2014, 15(4), 6757-6771; doi:10.3390/ijms15046757

Gentamicin Blocks the ACh-Induced BK Current in Guinea Pig Type II Vestibular Hair Cells by Competing with Ca2+ at the l-Type Calcium Channel

1,†
,
1,†
,
1
,
1
and
1,2,3,*
1
Department of Otorhinolaryngology, Union Hospital of Tongji Medical College, Hua-Zhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
2
Institute of Otorhinolaryngology, Union Hospital, Tongji Medical College, Hua-Zhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
3
Key Laboratory of Neurological Disease, Ministry of Education, Tongji Medical College, Hua-Zhong University of Science and Technology, Wuhan 430022, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 10 February 2014 / Revised: 3 March 2014 / Accepted: 9 April 2014 / Published: 22 April 2014
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Type II vestibular hair cells (VHCs II) contain big-conductance Ca2+-dependent K+ channels (BK) and L-type calcium channels. Our previous studies in guinea pig VHCs II indicated that acetylcholine (ACh) evoked the BK current by triggering the influx of Ca2+ ions through l-type Ca2+ channels, which was mediated by M2 muscarinic ACh receptor (mAChRs). Aminoglycoside antibiotics, such as gentamicin (GM), are known to have vestibulotoxicity, including damaging effects on the efferent nerve endings on VHCs II. This study used the whole-cell patch clamp technique to determine whether GM affects the vestibular efferent system at postsynaptic M2-mAChRs or the membrane ion channels. We found that GM could block the ACh-induced BK current and that inhibition was reversible, voltage-independent, and dose-dependent with an IC50 value of 36.3 ± 7.8 µM. Increasing the ACh concentration had little influence on GM blocking effect, but increasing the extracellular Ca2+ concentration ([Ca2+]o) could antagonize it. Moreover, 50 µM GM potently blocked Ca2+ currents activated by (-)-Bay-K8644, but did not block BK currents induced by NS1619. These observations indicate that GM most likely blocks the M2 mAChR-mediated response by competing with Ca2+ at the l-type calcium channel. These results provide insights into the vestibulotoxicity of aminoglycoside antibiotics on mammalian VHCs II. View Full-Text
Keywords: gentamicin; vestibular hair cells; big conductance calcium-dependent potassium channel; acetylcholine; calcium channel gentamicin; vestibular hair cells; big conductance calcium-dependent potassium channel; acetylcholine; calcium channel
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MDPI and ACS Style

Yu, H.; Guo, C.-K.; Wang, Y.; Zhou, T.; Kong, W.-J. Gentamicin Blocks the ACh-Induced BK Current in Guinea Pig Type II Vestibular Hair Cells by Competing with Ca2+ at the l-Type Calcium Channel. Int. J. Mol. Sci. 2014, 15, 6757-6771.

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